Immunologic and Fat-Associated Predictors of Insulin Resistance in Treated HIV

项目摘要 尽管现代抗逆转录病毒疗法（ART）大大提高了预期寿命，但艾滋病毒感染者 个体仍然比普通人群更容易患上包括2型糖尿病在内的许多疾病 糖尿病（T2DM）。虽然这种增加的风险似乎与持续的全身炎症有关， 尽管在初步研究中有抑制性ART，但介导这种效应的特异性免疫途径 仍然不清楚。 这项提案的长期目标是确定预测进行性免疫缺陷的免疫学特征。 胰岛素抵抗在HIV感染治疗中的作用现在有令人信服的证据表明，T2DM 一般人群中的发病机制是由年龄相关的慢性低度炎症引起的， 由常驻巨噬细胞驱动的白色脂肪组织（WAT），特别是在肥胖症的情况下。 有趣的是，体内WAT储存的重新分配和内脏肥胖的增加被认为是 通过抗逆转录病毒疗法（ART）维持病毒抑制的HIV感染者，以及一些 有迹象表明，一种可能类似于肥胖症的慢性炎症， 在慢性HIV感染的情况下，即使在非肥胖个体中，也会出现免疫重建引起的疾病。 利用艾滋病毒感染者纵向队列（SCOPE）， 该建议的目的是使用系统的、脂肪组织特异性的和尖端的放射线成像 用于识别进行性葡萄糖调节异常的组织特异性、细胞和分子生物标志物的工具， 特别关注促炎性骨髓细胞亚群。目的是找到免疫学特征 这些与T2 DM事件密切相关，并且还预测血糖控制会随着时间的推移而恶化。 这一建议的影响在于它有可能确定介导免疫系统疾病的特定免疫途径。 在接受治疗的HIV感染者中，T2DM的风险增加，以确定新干预措施的目标。

Project Summary Despite dramatic improvements in life expectancy with modern antiretroviral therapy (ART), HIV-infected individuals remain at higher risk than the general population for many morbidities including type 2 diabetes mellitus (T2DM). While this increased risk appears to be associated with persistent systemic inflammation despite suppressive ART in preliminary studies, the specific immunologic pathways mediating this effect remain unclear. The long-term goal of this proposal is to determine the immunologic signatures that predict progressive insulin resistance in treated HIV infection. There is now compelling evidence to indicate that T2DM pathogenesis in the general population is spurred on by age-related chronic low-grade inflammation in the white adipose tissue (WAT) that is driven by resident macrophages, particularly in the context of obesity. Interestingly, a redistribution of WAT stores within the body and an increase in visceral adiposity is seen in HIV-infected people where viral suppression has been maintained by antiretroviral therapy (ART), and several indicators highlight that a form of chronic inflammation potentially analogous to that seen in obesity is also brought on by immunological reconstitution in the setting of chronic HIV, even in non-obese individuals. Leveraging an exceptionally well characterized longitudinal cohort of HIV-infected participants (SCOPE), the objective of this proposal is to use systemic, adipose tissue-specific, and cutting-edge radiographic imaging tools to identify tissue-specific, cellular, and molecular biomarkers of progressive glucose dysregulation, with a particular focus on pro-inflammatory myeloid cell subpopulations. The aim is to find immunologic signatures that are strongly associated with incident T2DM and that also predict worsening glucose control over time. The impact of this proposal lies in its potential to identify specific immunologic pathways that mediate the increased risk of T2DM in treated HIV infection to identify targets for novel interventions.